Alzheimer's disease (AD) is the most common neurodegenerative disorder characterized by progressive memory loss and cognitive dysfunctions. These clinical features are thought to arise from age- related, progressive loss of cortical neurons and processes. Synaptic dysfunction is widely thought to be an early pathogenic alteration before frank neurodegeneration in AD, but the underlying mechanism remains to be elucidated. Mutations in the presenilin (PS) genes account for ~90% of all identified causative mutations in familial AD, highlighting the importance of PS in the pathogenesis of AD. Through the development and multidisciplinary analysis of a series of PS mutant mice, we have previously established the physiological functions of PS in the central nervous system. In the adult cerebral cortex, presenilins play a central role in memory, synaptic plasticity and neuronal survival. Our analysis of PS conditional double knockout (PS cDKO) mice demonstrated that inactivation of both presenilins in the postnatal forebrain results in memory and synaptic plasticity impairments followed by progressive neurodegeneration. Further genetic dissection revealed that presynaptic presenilins play an essential and selective role in neurotransmitter release and long-term potentiation and in ryanodine receptor (RyR)-mediated calcium release from intracellular calcium stores. In this competing renewal application, we hypothesize that presenilins interact with RyRs directly to regulate calcium homeostasis in the cell, and that loss of PS disrupts calcium homeostasis in the ER/mitochondria, leading to impairment of synaptic function and apoptotic cell death. To test this hypothesis, we propose the following two Specific Aims. First, we will investigate the role of PS in the regulation of calcium homeostasis. Specifically, we will determine whether loss of PS affects calcium concentration and homeostasis in the ER, mitochondria and synaptic terminals in cultured hippocampal neurons. Second, we will investigate the mechanisms by which presenilins regulate synaptic function and neuronal survival. Specifically, we will determine how presenilins interact with RyRs in the regulation of synaptic function, and whether restoring RyR function can rescue the synaptic dysfunction and increased apoptotic cell death caused by loss PS function. The completion of the proposed study will provide mechanistic insight into how presenilins regulate calcium homeostasis, synaptic function and neuronal survival. Our long-term goal is to understand the pathogenic mechanism underlying synaptic dysfunction and degeneration caused by loss of presenilin function, and to characterize the cellular and molecular pathways responsible for AD pathogenesis. PUBLIC HEALTH RELEVANCE: Alzheimer's disease (AD) is the most common neurodegenerative disorder, and mutations in the presenilin genes are the most common cause of inherited forms of the disease. Synaptic dysfunction is widely thought to be the pathogenic precursor to neurodegeneration in AD. In this application, we proposed to study the mechanisms by which presenilins regulate synaptic function. Completion of our proposed study will provide insights into AD pathogenesis and may identify novel therapeutic targets for development of new drugs.